Ultimately, we seek to understand how saliva of arthropods contributes to the interaction of vectors with vertebrate hosts, and to the interaction of vectors with their parasites. Toward this end, we shall investigate anti-clotting, anti-platelet, vasoactive, anti-inflammatory, and cytostatic properties of vector saliva, characterizing them both pharmacologically and biochemically. Mosquitoes, triatomine bugs, and sand flies will be included in these studies. In particular, (1) the mechanism of action of several known salivary activities will be investigated, as follows: The anti-factor VIII activity of Rhodnius prolixus will be studied. The interactions of Rhodnius nitrophorin with cysteine and nor-epinephrine will be characterized. The kinetics and biological role of the NADPH- oxidase/superoxide production in Anopheles albimanus salivary glands will be investigated. (2) Known activities from salivary glands of blood sucking arthropods will be purified and characterized molecularly, such as a third anti-platelet activity of Rhodnius prolixus, and the salivary peroxidase and apyrase activities of An. albimanus. The salivary apyrase of Triatoma infestans will be characterized, purified, cloned, and compared to that of Aedes aegypti and Rhodnius prolixus, allowing the comparative study of sequence similarity among different species of triatomine bugs and other blood sucking arthropods. (3) Novel anti-hemostatic and anti-inflammatory compounds will be searched for. Novel anticlotting substances from triatomine bugs will be screened and their action in specific locations of the clotting cascade characterized. Selected anti-clotting compounds will be purified and characterized molecularly. Antineutrophil adhesion molecules will be searched for in the saliva of mosquitoes, sand flies and triatomine bugs. (4) Finally, we will characterize molecularly the activity inducing a cytostatic effect for Leishmania found in the salivary glands of the sand fly Lutzomyia longipalpis. This work explores the hypothesis that saliva of hematophagous arthropods mainly serves an antihemostatic and antiinflammatory role during blood- finding and blood-feeding. As we extend this work, it is our hope that this line of research will contribute meaningful information to other entomologists, parasitologists and immunologists, seeking to understand the mechanisms of pathogen transmission by vectors, and by pharmacologists, in their quest for more powerful and useful drugs.